Ultrasmall Cu2-XS nanodots as photothermal-enhanced Fenton nanocatalysts for synergistic tumor therapy at NIR-II biowindow

Reactive oxygen species (ROS)-mediated nanocatalytic therapy, as conducted by the tumor microenvironment to generate toxic hydroxyl (center dot OH) radicals with the assistant of Fenton nanocatalysts, exhibits high tumor-therapeutic promise due to its high therapeutic selectivity and desirable therapeutic outcome. The mostly explored Fe-based Fenton nanocatalysts-enabled nanocatalytic cancer therapy substantially suffers from lowed pH condition and the corresponding therapeutic effect is still far from satisfactory for further clinic application. In this work, we report, for the first time, that copper (Cu)-based nanocatalysts have the intrinsic capability to catalyze hydrogen peroxide (H2O2) into hydroxyl radicals in a wide range pH condition with the comparable and even better performance as compared to mostly explored Fe-based nanocatalysts. Especially, ultrasmall (<= 5 nm) PEGylated Cu2-xS nanodots (Cu2-xS-PEG) were fabricated to serve as the novel Fenton nanocatalysts for nano catalytic tumor therapy. Importantly, taking the unique advantage of high near infrared (NIR) light absorbance at NIR-II biowindow (1000-1350 nm), light-activated photonic theranostic modality, i.e. photoacoustic imaging and photothermal therapy at both NIR-II biowindows was introduced, which could efficiently delineate/monitor the tumor regions and synergistically enhance Fenton-mediated therapeutic efficacy by photonic hyperthermia, respectively. Both systematic in vitro and in vivo experiments have demonstrated the high therapeutic efficacy of Cu2-xS-enabled synergistic photothermal hyperthermia-enhanced nanocatalytic therapy. This work not only provides a nanoparticle-augmented synergistic cancer-therapeutic modality, but also enriches the totally new nanocatalyst types for catalytic Fenton reaction-based nanocatalytic tumor therapy.